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Digimon Masters Opens New Server Beelzemon
887d ago - Joymax today announced a new server that will be added next week for its popular MMORPG, Digimon... | PC
Digimon Masters Reveals New Digimon With Massive Update
911d ago - Joymax, a leading online game developer and publisher of free to play MMORPGs, today revealed the... | PC
This October's Releases For All Things PlayStation
Now - The spooky month of October is almost upon us and that means another calendar month of releases to feed our gamer appetites. We take a look at what... | Promoted post
Digimon Masters Unveils File Island
915d ago - Joymax, a leading online game developer and publisher of free to play MMORPGs today previews an u... | PC
Silkroad Online - Ignite Silkroad - Elevation
1057d ago - Joymax today announces a new expansion for their anchor MMORPG, Silkroad Online. Named "Ignite Si... | PC
Knight Age Officially Launches September 3
1129d ago - Joymax, leading online game developer and publisher widely known for Silkroad Online and Digimon... | PC
Joymax & Community Donate To Turkey Earthquake Relief Efforts
1425d ago - Joymax and its community have come together to raise a large donation for the Red Cross Relief Ef... | PC
Joymax Invites Experienced Players To Test Silkroad Online
1565d ago - Joymax, Korean developers and publishers of interactive entertainment for the global market, anno... | PC
Karma: Prisoners of the Dead- Info, Screenshots and a Trailer
1580d ago - Karma: Prisoners of the Dead, developed and published by Korean company Joymax, announced the sta... | PC
Joymax to showcase seven titles at GDC'11
1683d ago - Online game developer and publisher Joymax is unveiling seven gaming titles during this year's Ga... | PC
Merger announced for Joymax and WeMade
1687d ago - Online game publishers Joymax and WeMade Entertainment have announced a merger today, bringing th... | Industry
'Special Force' and 'KARMA Returns' are coming West
1710d ago - Joymax are to partner up with top Korean online game developer - Dragonfly - to bring two of thei... | Industry
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6000 Shepherd Mountain Cove
Austin, Texas, 78730
Commute to Downtown Austin
Almost all errands require a car.
It is possible to get on a bus.
Very steep hills, minimal bike lanes.
Score Details
6000 Shepherd Mountain Cove has a Walk Score of 9 out of 100. This location is a Car-Dependent neighborhood so almost all errands require a car.
This location is in Austin. The closest park is Bull Creek Park.
Explore how far you can travel by car, bus, bike and foot from 6000 Shepherd Mountain Cove.
6000 Shepherd Mountain Cove compared to all of Austin.
Lower crime area.
Lowest crime area.
How do you feel walking near 6000 Shepherd Mountain Cove?
Thanks for your feedback!
This location is in the city of Austin, TX. Austin has an average Walk Score of 35 and has 790,390 residents.

subset: commoncrawl


text:
Re: Snowy Owls today in Polson/Pablo
Expand Messages
- Searched for snowy owls this afternoon (Sat. 31 Dec) from Ninepipe NWR north on backroads to Polson.....only saw one (see below). Did not see these email posts about the birds in Polson until I got home (!) However, when we were at Pablo NWR, standing on the dam, a snowy owl flew in from the north, circled the reservoir at about 200-300 ft. elevation then flew back straight north until it was out of sight. Plotting on GoogleEarth it looks like the trajectory of the owl as it flew north was almost directly toward these Polson water towers (only 2 miles away as the owl flies).
--- In email@example.com, "Jan" <jan@...> wrote:
> I saw 3 of them on top of Polson hill. The weather was cold and cloudy all day, but took a few pics anyway which I posted. I made up an email with directions from north or south and Google maps showing the locations. If anyone is interested, just email me.
> Jan
Your message has been successfully submitted and would be delivered to recipients shortly.


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McButter777's Mom Answers Activity
Everyone tells me horror stories about childbirth. Should I ask them to stop?
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of course you want to give her toys just out of her reach but also get on the floor where your at her level and let her watch you then pr...posted by tolercassie


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Maldron Hotel Cork
No prices found through our partners. Please contact the business directly or check some of our recommended alternatives.
How has this hotel rated in the past?
- Adjoining Rooms
- Restaurant
- Free High-Speed Internet
- Swimming pool
- Breakfast Available
- Room service
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Historical Traveler Reviews Maldron Hotel Cork
Not A Happy Stay
I have stayed here twice now and each time I've had problems. One of the worst things about this hotel is that it only has one really small elevator for over 100 rooms. If families are staying on the upper floors then the chances of getting down quick are very slim. Buggy-pushing parents beware! You will be waiting a while until you get the empty elevator which only holds two people and a buggy! Members of my family who stayed on a different floor to me had shouting in the room next to them for over an hour at 3am and I have had the experience of people running up and down hallways shouting the last time I stayed there. Staff seemed very lax about checking people in and the staff attitude in general was pretty poor. My parents weren't able to check in until 4pm, despite being told they could do it at 2pm, because the lady at the desk said the rooms were still dirty and being cleaned!
Lastly, this hotel is not very good value and I won't be returning.
Good city hotel
I have recently returned after a 2 night stay. The hotel is situated over the river about a 5 minute walk to the main shopping/eating areas of Merchant Quay and Patrick Street. There is a slight short hill before reaching the hotel which may affect those with walking difficulties or those with luggage (would recommend you get a taxi from the airport and not the bus - taxi is €13 - €15 one way dependent on traffic).
The reception staff were pleasant and helpful and the lounge and bar area "Bells Bar" are well decorated and furnished although small. We had an early dinner in the bar one night before leaving for the airport and took advantage of their special offer of any meal choice plus a pint for €10.00 or a soft drink for €9.00
Meal choices include cajun chicken bap, fish & chips, steak burger + fries etc. Standard pub food - no complaints with very quick service.
Breakfast was served in their Lannagan's restaurant and was self service with a choice of pastries, cereals, toast or cooked breakfast. Tea and coffee was served by the waiters and juices were self service.
Rooms were nicely decorated (dark wood / dark colour scheme) with two chairs, small table, wardrobe, vanity table, tv and tea/coffee making facilities. No safety deposit box in the room. The bathroom was a good size and had a bath with a built in shower over it. No problem with cleanliness in our room.
Did not try Club Vitae - their spa & fitness centre although it seemed popular with the locals.
Decent location, Helpful Staff.
My husband and I stayed at Quality Inn Cork for one night during our trip to Ireland. We selected the hotel because of its proximity to the Blarney Castle which we were travelling to the next morning. (Blarney Castle is only about 15 minutes away.)
Another bonus of the location is that it was only about a 5-10 minute walk from the City Centre. We walked there in the evening to enjoy pubs and live music on Paul Street.
We appreciated that the hotel had free parking and that the front desk staff were all very knowledgeable about the area and free with advice on how to get from point a to point b.
The rooms were very simple, no frills. They were not the cleanest either. The common areas of the hotel (lobby, restaurant, etc.) were very nice though. My biggest complaint about this hotel is that for what it was, it was quite overpriced. I would describe this hotel as a "budget accommodation", but at $150 (USD) it was hardly a budget price.
If you do stay in Cork, it is worth a visit to St. Anne's Church. (Located directly across the car park from the Quality Inn.) For 6 Euro you can explore the historical church and, here is the best part, you can ring the church bells. They provide little song sheets that tell you which bells to ring in which order. You can play anything from "You are My Sunshine" to "Amazing Grace." Your song rings out all over Cork. Plus, the view from the top of the bell tower is spectacular. I have attached a photo of the view.
One word of caution, you must climb many, many steps (which are also very narrow) to experience St. Anne's Church. Not recommended if you are not in good shape.
Well Improved
Revisited the Quality Hotel following a not-very-good stay earlier in the year. Must commend staff and management on the vast improvement. Though the rooms and decor were still of a high standard, the real work has gone on upgrading the menu particularly for children. The kids loved their proper (not just chips etc.) food and we almost envied them! Top marks alround! Very good value for money, especially with a number of children in tow.
Great Hotel
Stayed there for two nights, clean rooms, good fully cooked buffet brekky, great bar and a swim and sauna to wash away the excess!! Paid 98 euros per room per night including brekky for two.
None of the dubious characters mentioned elsewhere were spotted, just a quiet part of town I think?
Pop into the wee bar down the hill on the way to town who's name escapes me (Buckleys??) and have one of the best pints of Murphy's in Cork (no groups).
For food, head to Scuzzi's (sp?) in town for good affordable food.
Excellent value
very near to city centre but bit of a hill. Excellent room very clean with everything you needed. Staff were all very good. Bar is ok and has a good deal of a meal and drink for ten euros. Plenty of places to eat and drink within five minutes. Would stay again , also we did not see any bad characters near by.
All positive
Myself and my girlfriend stayed in This hotel for 3 nights from the 28th March 2005. It is an excellent hotel and I cant understand anyone being negative in their reviews. The hotel is spotless and great value for money. The staff couldnt have been nicer and the leisure centre is a bonus. Definitely be back here. No doubt.
Hmmm not impressed
Me and my partner stayed at this hotel for 4 nights from 17th Feb. It cost us approx �100 a night, so for this we were expecting great things. Our room was clean but a bit shabby, duvet cover had holes in it, floor tiles in bathroom cracked, and room very small. Our bathroom was designed as a wet room, and it meant when you had a shower water went absolutely everywhere, and didnt drain away, to the point where it actually ran into the bedroom! Very noisy in the morning, think maybe we were above the kitchen? and could hear everyone walking past the room and their conversations, which meant no chance of a lie in! Location is good, about a 10 minute walk to Patrick street. Lesiure centre very nice and an good asset. Bar pretty expensive and majority of staff pretty miserable. Didnt go to restaurants in hotel so cant comment. Iwould not stay here again unless i got a very good deal i would say it is a hotel worth around €65 a night. definately not a 3* hotel (compared to English and most other European hotels). If you took away the leisure facilities i would say it is of a lower standard than a Travel Lodge.
Went to Cork for three nights for the Jazz festival, I got it for a fantastic price through ebookers - 274 € for the whole weekend for me and my boyfriend.
The room was a bit small but who cares your hardley in it at all. We had breakfast every morning, room service of course and it was lovely, bit pricey i thought though at €9 a head plus €2 each for service, but hey we were on holidays!!
We also ate dinner there on one of the nights and it was fab and there was a lovely jazz band playing as we ate.
The staff cannot do enough for you there either, really lovely and helpful.
The hotel is less than a five minute walk from patrick street which was deadly as even though it did say it was a five minute walk from the hotel on there web site, i was still Skeptical.
All in all a great hotel in a great location, the only complaint was the shower was broken but we had a bath so i didnt mind too much.
Good choice, centrally located, though off the main streets. Clean, warm and comfortable, though a little squeeky clean as newly developed when I visited. Fire doors make an awful noise 1st thing in the morning! Generally well recommended and a friendly, warm welcome throughout; good atmosphere in the bar in the evenings. Good quality breakfast for all tastes. Check out the Buttermarket and Shandon Church at the back of the hotel.
TripAdvisor Reviews Maldron Hotel Cork
Travel Blogs from Cork
Kilkenny to Kinsale. Day3
... off this coastline was the sinking of the Lauritania by a German U boat, which brought the Americans into the war. Like so many of the Irish villages the flower pots are just gorgeous. This one had huge pots of bright yellow and orange Begonias - thought of you Di. I We drove through Cork but was a very large fairly ordinary town when we are spoilt by all the other ones we visited,and decided to move on to our next stop Blarney Castle. From the top ...
The First Pancake
... had a couple of hours and you can bet that we did everything.
The walk up to the Blarney stone was also very surprising. Here you had to climb up small, slippery, windy stairways to the top of the castle. It was much higher than expected, but it was so cool. Julia was freaking out and almost didn't kiss the Blarney Stone because she's scared of heights, but she was so glad that I made her do it. Putting my life into the hands of some random guy who sits on the roof of ...
Sunny Saturday go braugh
... photo and a small hike. Blackbird pub for a hot toddy with clove and a pint. Relaxed. Sat. And enjoyed good company. Each moment we are lucky. Next stop "fantasy land". Without depth and arduous detail. Just imagine Alice in wonderland, the Crown Jewels, French laundry, storm king, Narnia, and everyone you love, under one roof- surrounded by ...
We'll Take Two
... we agree to drop him off. It's not even noon yet and already we've had quite an eventful day.The windows are all down as we head into Cork, but the smell of vomit is not disappearing, it's like a toxic gas. Chris is probably relieved to get out of the car when we pull into the Qualcomm complex. The rest of us, have to sit in the stinky car a bit longer. We drop off the roof box and stop at the store, we need an air freshener, 4 to be exact.
Cork, Ireland and surrounding towns
... disastrously tried to over throw the King of England, and took the whole town down with him. The city was originally built as a monastic community in the 6th century but quickly became a center for trade. Nowadays, this major Irish seaport is also an international tourist destination with many interesting sites.
Along the River Lee, you can admire ...


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Fantastic FalafelsPosted on 07 / 20 / 2012
Pita Place is without a doubt, the best, consistently delicious option for vegetarian food in Fairbanks. Everything that is served there is fresh and vegetarian! When possible, they use fresh, organic veggies purchased that day at the farmers market. Delicious, freshly made pitas, fantastic falafel, and the best spicy harif sauce I've ever had. Dropping in for a "full falafel with everything" has become a hugely popular and valued summer tradition with Fairbanksians, especially combined with a trip to the Saturday Farmers Market! Pita Place is only open in the summer between Wednesday and Saturday.
Cons: only open in summer


text: Slideshows Published On: Jun 22 2012 07:04:45 PM EDT Updated On: Jan 25 2013 11:28:12 AM EST Michigan's most haunted locations Notable deaths of 2015 FIFA corruption scandal: What you need to know Forgotten by the Rock and Roll Hall of Fame Which presidential candidate's supporters have worst grammar? Sexiest celebrity vegetarians Red Bull Global Rallycross Detroit Remembering John Lennon On this day: October 9 Slipknot Comes Back to Detroit Slideshow: Famous Michiganders in black history 7 food mashups that seem gross but are tasty Historical 'facts' that we get wrong 2015 Nobel Prize winners NFL players in trouble with the law On this day: October 8 Late night TV hosts through the years Orphaned baby brushtail possum snuggles with toy kangaroo Yogi Berra's long and storied baseball career Celebrities who have battled cancer Roles of Zac Efron 12 things you didn't know about dogs Kristen Stewart through the years 2016 Rock and Roll Hall of Fame finalists On this day: October 7 Films of Tom Hardy Most 'dangerous' celeb web searches of 2015 Can you guess the celebrity eyes? Past Nobel Peace Prize winners Films of Jeremy Renner View More


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BPL Community Profile
Nathan Watts (7sport) - BPL Lifetime Member
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All Forum Posts by Nathan Watts
Showing 161 - 170 of 733 | Page: 1 ...8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 ...74
Re: Re: So what is the deal with rain pants?
"I wear rain pants if I am expecting a lot of rain at temps close to freezing. They are invaluable then." Same with me
WTB Inov-8
Looking for the following: 2012 Roclite 295 X-talon 190 (any year) Size 10 or 10.5 New or Used and willing to pay cash (PayPal) or trade for them For trades ive got a couple pairs of br...
Re: Ibex Indie Hoody too Hot for Summer in the Sierras?
For me personally, I'd die trying to hike in an ibex indie hoodie at 85 degrees. Even standing around would be quite uncomfortable. I'd definitely pick something lighter
Re: FS: RailRiders Women's Adventure Shirt, Medium, Khaki
"Are you interested in the shirt or were you just being helpful?" I am in fact interested for my wife. Not sure if she'll go for the color, but at $22 I think it's worth a try....
What are the stains on the front of the shirt?
Re: Buying a second sleeping bag...or is it time for a quilt?
I'd definitely choose the Summerlite option. I have one and love it. Not much weight to be saved by going with a quilt, and the bag can be opened up and used like a quilt if you want. If it...
Dialed In
I'm finally pretty happy with my pack and shelter options. I've got a WPB bivy for light and fast overnight or weekend adventures when decent weather is expected or I'm planning on ...
Re: Easton Kilo vs Tarptent Double Rainbow
I bought and returned a Kilo. Was too small for two in my opinion. I have no experience with tarptents, but people here seem to really like them. I really like Big Sky tents. Might require...
Shelter is sold pending payment
All Reader Reviews by Nathan Watts
Nathan Watts has posted no reviews.


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2011 Performance Review 1 commentJan 8, 2012 4:46 PMMy performance this year was awful. The only bright spot was total trading, which was way down. In all other areas I underperformed and lost out. My portfolio lost nearly a quarter of its value this year, even as the market stayed flat. This was mainly because I tried to time the market and failed. My average losses reflected this fact in that my average loss on positions held for two weeks or less was 16% greater than the average loss on positions held for less than one month. Nearly all of the positions I closed this year lost money. This represents a fundamental flaw in my approach: I have been too aggressive and I have not taken the time to learn about my companies. Going forward, this is an issue that I must address.The only bright spot (I guess) was the amount of trading I did. I executed 35 trades in 2011, down from over 100 in 2010. My average holding period also increased from 26 to 57 days, although this fails to acknowledge positions I still hold (which would increase the value for 2011). A large percentage of my poor performance was contributed by the third quarter, when I tried to time the market numerous times, only to fail.
Going forward, I plan to protect myself from myself by letting my portfolio rest. I have increased my bond exposure by 10%, moving into a high yield fund. I like my holdings, and I need to be more patient.
Back To Charlie Anderson's Instablog HomePage »
Instablogs are blogs which are instantly set up and networked within the Seeking Alpha community. Instablog posts are not selected, edited or screened by Seeking Alpha editors, in contrast to contributors' articles.Comments (1)Track new comments
Full index of posts »
Charlie it's good to see someone have the jam on here to talk about their misses as while as their hits. If I could offer any advice, i cannot emphasize enough the use of the NYSE McClellan Oscillator to aid in entry points. It is excellent to determine market bottoms. Keep at it and good luck.
FSLR is approaching the bottom end of its range between 100 and 150. May 26, 2011
GES broke out of the symmetrical triangle formation today on 1st quarter results. May 26, 2011
GES is near the upper limit of a large symmetrical triangle formation, and will hopefully break out to the upside. May 17, 2011
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text:
United States & Canada Customers: Call 1-800-813-6897
Available 24 hours a day, 7 days a week.
International Customers: Call 1-512-837-4810
Available 24 hours a day, 7 days a week. English language only.
TaylorMade SLDR Mini Driver: Finally, a 3-wood Designed for the Tee
TaylorMade created a new golf club that incorporates their cutting edge metalwood technology, including the distance-enhancing Speed Pocket, and sized it between a 3-wood and 460cc driver. It�s incredibly accurate and longer off the tee than a 3-wood. At 260cc, the SLDR Mini Driver�s footprint is larger, and face deeper, than a 160cc 3-wood. That gives you more stability and forgiveness on mis-hits and allows you to tee the ball higher, which makes the it easier to launch off the tee than a 3-wood. The SLDR Mini Driver has a low-forward CG like the rest of TaylorMade�s SLDR metalwoods, and a Speed Pocket too, which promotes more ball speed and less spin to give you more distance when you loft up.
In addition, the SLDR Mini Driver�s relatively short shaft (43.5" compared to 45.5" for the average driver) gives you the added clubhead control necessary to help you hit the ball straighter. There�s more. The Mini Driver�s sole, smaller than a driver�s, is designed to make it easy to hit this club off the deck. That�s why, even though it�s called a SLDR Mini Driver, you�re going to want to replace your 3-wood with it. Then you�ll have a great option for long, accurate tee shots when placement in the fairway is vital. And you've got the perfect club for getting home in two on those previously unreachable par-5s. Because everything that makes the SLDR Mini Driver long and accurate off the tee makes it long and accurate off the turf too.
We noticed that Tour pros and better amateurs hit their 3-wood off the tee a lot more frequently than from the fairway, so we embraced that insight and used our cutting edge metalwood technology to create a club that is designed for the tee, with a size that fits in between 3-wood and driver. - Brian Bazzel, TaylorMade Senior Director - Metalwood Product Creation
Additional features:
Online Shipping Information
Golfsmith.com offers simple, flat-rate shipping to destinations in the continguous U.S. via FedEx.
Our policy is to strive for the best possible combination of price and service for your shipment.
In order to better serve our guests, we will occassionally offer discounted shipping promotions. Any shipping discounts will be applied in your shopping cart.
"Overnight" shipments will arrive the next business day (excluding weekends and holidays) after departing Golfsmith. "2-Day Air" shipments arrive in two business days after departing Golfsmith. On-time delivery for both methods is guaranteed by FedEx. Shipping delays may occur during busy Holidays or in the spring -- we will do our best to accommodate last minute and expedited orders placed during these times.
Most orders are shipped within 48 hours of online placement. Orders must be placed by 9am (CST) Monday-Friday in order to be eligible for that day's "Overnight" or "2-Day Air" shipments. Orders for residential delivery placed on Sunday or Monday will not be shipped until Tuesday and orders for business delivery placed on weekends will not ship until Monday, so please take this into consideration when specifying expedited shipping requests.
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588 Precision Forged RTG Wedge
TAYLORMADEPriced Too Low to Show
SpeedBlade HL 4-PW, AW Iron Set with Steel Shafts$399.99
Blemished Tour Preferred WedgePriced Too Low to Show
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White Smoke Big Fontana Putter


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Robert Land
Robert Land is no longer a member of the WPJA and so their Member Profile cannot be accessed at this time.
The Wedding Photojournalist Association proudly recognizes the accomplishments and creative excellence of Robert Land. The following awards have been earned by Robert from the WPJA. These achievements come with great merit considering the high level of competition that a member faces in the contests.
|9th Place - Ceremony


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CanSing Choirs
Vancouver CanSing Community Choirs Online registration is now available for fall 2015, Sept 22 start:
Click the following for more information and registration:
VCS fall 2015 general information
LEVEL 1 (ages 5 – 6 – kindergarten, grade 1) FULL
LEVEL 2 (ages 7 – 8 – grade 2, 3) FULL
LEVEL 3 (ages 9 – 14, grade 4 – 10) FULL
Email: firstname.lastname@example.com for VANCOUVER LEVEL 1, 2, 3 WAIT LIST for information:
LEVEL 4 Auditioned (ages 10 – 16, grade 5 – 10)
ADULT CHOIR (mixed voices – SATB) Singers welcome
Contact: email@example.com
"A sincere thank you from Anna, Mark, Silvia and Luca for this pass semester. We enjoyed ourselves and the concert was amazing. We loved the mixed ages, voices, songs and audience participation." Silvia and Austin-Dotto clan
"It was wonderful! My thanks to you and Kevin. I am looking forward to "Spirit of Adventure."' Bonnie Mutton"What a great evening to enjoy the great indoors, while it poured outside! The standing O was icing on the cake!" David Vaisbord
"Thank you so much for a wonderful season of song, Gerda. I have loved every minute of the camaraderie, challenge and sense of real community." Caroline Nevin
"The kids were fantastic – the sound carried so well, even the soloists. And the choreographed numbers were so cute. The adult choir was flawless…. Brought tears to my eyes. Thanks for bringing so much joy to the neighbourhood." Beth Ringdahl
VCS Level 2 & 3 Audio Postcard
General VCS Info
VCS will provide opportunities to improve vocal skills through a variety of vocal collaborative settings including choir and musical theatre.
As a professional music educator and conductor, Gerda Blok-Wilson believes everyone CanSing but the teaching and learning process is technically and socially diverse depending on the experience of the singer. Including the classics, jazz, popular, gospel and world music, expressing the meaning of the words in a song is the key to developing as a singer. When the expressiveness of the words are understood and interpreted, engagement in the singing process flows authentically.
For the young singer, movement and acting skills are important, both of which are emphasized in the VCS format. In addition to the vocal technique and stage training that each singer will receive, the program will also build self-esteem, confidence and social skills.
All rehearsals will be held on Tuesdays at Cityview Church at 4370 Sophia Street.
Please do not make phone call inquiries to the church instead contact me.


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Should we keep the Bush tax cuts? The numbers indicate yes
Published: Wednesday, September 15, 2010 at 4:36 p.m.
Last Modified: Wednesday, September 15, 2010 at 4:36 p.m.
It is election time, the economy has not responded to a massive government stimulus program, and now some are saying that we should extend the much maligned Bush tax cuts to help stimulate the economy. The "tax cuts for the rich," when they expire, would pay for every spending program the Obama administration could come up with, pay down the debt and eventually create a utopian economy. We would have so much money that no working American who made less than $250,000 would have to pay higher taxes - not even for national health care. President Obama promised us. Now, why the change of heart? It is really about growing the economy, or it is about an election that is not going well for some. It doesn't take a genius to figure that one out.
Are the Bush tax cuts only for the rich? How does the Bush tax cut effect the average American? I went to websites like Forbes, read articles from Smart Money and Personal Finance and even The Washington Post to learn more. The results may surprise some people.
The two major tax-cutting bills from the Bush era were the Economic Growth and Tax Relief Reconciliation Act of 2001 and the Jobs and Growth Tax Relief Reconciliation Act of 2003. The two laws cut taxes across the board for earned income, long-term capital gains and dividends. The legislation doubled the child tax credit, reduced the marriage penalty, phased out the "death tax" and increased the threshold for the alternative minimum tax.
The Bush tax cuts created six tax rate brackets: 10, 15, 25, 28, 33 and 35 percent based on income levels. It Congress does not act, then the pre-2001 tax rates will go back into effect starting Jan. 1, 2011. The 10 percent bracket would disappear, and those taxpayers would move up to the 15 percent bracket, which would apply to all incomes below $34,550. The other tax rates would increase to 28, 31, 36 and 39.6 percent for the highest earners making more than $379,650.
Under the Bush tax cuts, the tax credit for each under the age 17 dependent child, stepchild, foster child or grandchild was increased from $600 to $1,000. The credit (as before) was phased out for high earners ($75,000 singles and $110,000 for joint filers).
Unless Congress votes to extend the child tax credit, the maximum amount will revert back to $500 for tax year 2011, and the number of families eligible for that amount will be much less as tougher eligibility standards that existed prior to the Bush tax cuts will go back into effect.
The maximum tax rate on long-term capital gains and qualified dividends under the Bush plan was reduced to 15 percent, with lower income filers facing a 0 percent tax rate. The old provisions would move the capital gains rate back to a maximum of 20 percent and qualified dividends would be taxed at the regular tax rate of the filer, or as high as 39.6 percent.
The Alternative Minimum Tax was developed 40 years ago to prevent wealthier Americans from zeroing out their taxable incomes with clever deductions and accounting tricks. Under the Bush tax policy, the AMT applies to families making more than $70,000 and individuals making more than $46,000 annually. Under the old tax rules, millions of Americans, families making more than $45,000 or more and individuals making at least $33,000, would be hit with the higher tax.
Before the Bush tax cuts, estates valued at more than $675,000 were taxed at the 55 percent rate. Starting in 2011, it will return to 55 percent with a $1 million exemption.
The phase out for itemized deductions was also eliminated by the Bush tax cuts, and these will also kick back in. Some taxpayers may lose as much as 80 percent of their itemized deductions if their incomes are too high.
We will be hearing much debate in this election cycle regarding which cuts to keep and which ones to rescind. The most likely scenario is that President Obama and the Democrats will promise to keep the rates for lower and middle class but will once again raise the rates for Americans making more than $200,000 for individuals and $250,000 for families. Sound familiar?
Keynesian economic policies have failed miserably the last two years. Consumers need disposable income to spend to help create jobs, including consumers that make more than $250,000 a year. Tax breaks for businesses, large and small are very helpful and will aid in expanding the economy, but it is the consumers who need money in their pocket to spend, save or invest. People also need certainty, which allows them to plan for major spending purchases for items like homes, cars and appliances. Low or no capital gain taxes will increase investments in business, provide start-up capital for new businesses and allow existing businesses to expand.
The Bush tax cuts should not be extended temporally but made permanent. The rapid depreciation provisions for small business should be brought back. Yes, those who make over $250,000 benefit, but so does all the working class. This is the kind of "stimulus" that gives consumers confidence to invest in our economy and create jobs.
Dwight D. Cornelison is a former small business owner and Thomasville City Councilman 1999-2007.
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text:
Page 1
published: 16 May 2012
doi: 10.3389/fphar.2012.00091
Increasing the clinical efficacy of NK and
antibody-mediated cancer immunotherapy: potential
predictors of successful clinical outcome based on
observations in high-risk neuroblastoma
TonyA. Koehn1†, Lori L.Trimble1†, Kory L.Alderson1,Amy K. Erbe1, KimberlyA. McDowell1, Bartosz
Grzywacz2, JacquelynA. Hank1,3and Paul M. Sondel1,3,4*
1Department of Human Oncology, University of Wisconsin Madison, Madison, WI, USA
2Department of Pathology, University of Wisconsin Madison, Madison, WI, USA
3Paul P . Carbone Comprehensive Cancer Center, University of Wisconsin Madison, Madison, WI, USA
4Department of Pediatrics, University of Wisconsin Madison, Madison, WI, USA
Edited by:
Alexandre Arcaro, University of Bern,
Reviewed by:
Todd Skaar, Indiana University Medical
Center, USA
Francois M. Vallette, Institut National
de la Santé et de la Recherche
Médicale, France
Paul M. Sondel, Paul P . Carbone
Comprehensive Cancer Center,
University of Wisconsin Madison,
4159 MACC Fund UW Childhood
Cancer Research Wing, WIMR, 1111
Highland Avenue, Madison, WI
e-mail: email@example.com
†Co-first authors.
Disease recurrence is frequent in high-risk neuroblastoma (NBL) patients even after multi-
modality aggressive treatment [a combination of chemotherapy, surgical resection, local
radiation therapy, autologous stem cell transplantation, and cis-retinoic acid (CRA)]. Recent
clinical studies have explored the use of monoclonal antibodies (mAbs) that bind to disialo-
ganglioside (GD2), highly expressed in NBL, as a means to enable immune effector cells
to destroy NBL cells via antibody-dependent cell-mediated cytotoxicity (ADCC). Preclinical
data indicate thatADCC can be more effective when appropriate effector cells are activated
by cytokines. Clinical studies have pursued this by administering anti-GD2mAb in combina-
tion with ADCC-enhancing cytokines (IL2 and GM-CSF), a regimen that has demonstrated
improved cancer-free survival. More recently, early clinical studies have used a fusion pro-
tein that consists of the anti-GD2mAb directly linked to IL2, and anti-tumor responses
were seen in the Phase II setting. Analyses of genes that code for receptors that influence
ADCC activity and natural killer (NK) cell function [Fc receptor (FcR), killer immunoglublin-
mine whether these genotypes can be used as predictive markers for favorable therapeutic
outcome. In this review, we discuss factors that affect response to mAb-based tumor ther-
apies such as hu14.18-IL2. Many of our observations have been made in the context of
NBL; however, we will also include some observations made with mAbs targeting other
tumor types that are consistent with results in NBL. Therefore, we hypothesize that the
NBL observations discussed here may also be relevant to mAb therapy for other cancers,
in which ADCC is known to play a role.
Keywords:ADCC, KIR, FcR, neuroblastoma, immunocytokine, mAb, IL2
Neuroblastoma is the most common extracranial solid tumor in
children, accounting for 8–10% of all childhood cancers with
approximately 600 new cases diagnosed in the United States
Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; AIS, acti-
vating immune synapse; AML, acute myeloid leukemia; ALL, acute lymphoid
leukemia; ASCT, aAutologous stem cell transplant; CD16, FcRγIIIa; CD20, B-
lymphocyte antigen expressed on all mature B-cells; CD32, FcRγIIa; ch14.18,
acid; CRC, colorectal cancer; EGFR, epidermal growth factor receptor; F, pheny-
lalanine; FcR, receptor for Fc region of immunoglobulin; GD2, disialoganglioside;
GM-CSF, granulocyte macrophage colony stimulating factor; H, histidine; HER2,
human epidermal growth factor receptor-2;HLA,human leukocyte antigen;HSCT,
hu14.18-IL2, humanized 14.18-IL2 IC; IC, immunocytokine; IFN-γ, interferon-
γ;IL2, interleukin 2; IL2R, IL2 receptor; KIR, killer immunoglobulin-like receptor;
each year (Navid et al., 2009). Greater than 60% of patients
older than 1year of age have metastatic tumors (Modak and
Cheung, 2007), and for these high-risk patients, the prognosis
is often poor. Even with the aggressive multi-modal treatment
KIR-L, killer immunoglobulin-like receptor ligand; K-ras, Kirsten rat sarcoma
oncogene homolog; mAb, monoclonal antibody; MHC-I, major histocompatibil-
ity complex class I; MIP-1α,macrophage inflammatory protein-1α; MRD,minimal
residual disease; NCRs, natural cytotoxicity receptors; NBL, neuroblastoma; NK,
natural killer; NKG2A/CD94, inhibitory NK cell receptor, a dimer of NKG2A and
CD94; NKG2D, activating NK cell receptor; NKL, NK-like cell line expressing
little or no CD16; PCR-SSP, PCR amplification with sequence-specific primers;
PCR-SSOP, PCR amplification using a sequence-specific oligonucleotide probe;
R, arginine; RANTES, regulated-upon activation, normal T expressed cytokine;
SBT, sequence-based typing; SNP, single nucleotide polymorphism; TNF-α, tumor
necrosis factor-α;V, valine.
May 2012 | Volume 3 | Article 91 | 1
Page 2
Koehn et al.KIR and FcR in clinical-ADCC
of surgery, chemotherapy, radiotherapy, CRA, and autologous
stem cell transplantation (ASCT), the recent (as of 2010) 3-year
event-free survival remained as low as 30%, often due to recur-
rence caused by refractory minimal residual disease (MRD; Yang
and Sondel, 2010). More effective treatment strategies are highly
sought, including advances via immunotherapeutic options (Yu
et al., 2010), currently being further developed in clinical trials.
Neuroblastoma is a tumor of neuroectodermal origin and
overexpresses GD2. Since GD2expression is restricted to few nor-
mal tissue types, such as peripheral nerves, and its normal level
of expression is relatively low, it is a viable target for tumor-
selective immunotherapy involving anti-GD2monoclonal anti-
from fully murine (3F8 and 14.G2a) to chimeric (ch14.18) to
humanized (hu14.18) reagents. One recent preclinical develop-
ment in anti-GD2immunotherapy is an antibody that recognizes
the O-acetyl derivative of GD2 (OAcGD2; Alvarez-Rueda et al.,
2011). Preclinical and clinical testing is also proceeding with
hu14.18-IL2,animmunocytokine(IC)comprisedof ahumanized
form of the anti-GD2mAb genetically linked to two molecules of
These immunotherapies exploit the cytolytic activities of NK cells
via CD16, the FcR found on NK cells, which can cause antibody-
dependent cell-mediated cytotoxicity (ADCC) upon binding to
the Fc portion of such mAbs or ICs (Weiner et al., 2009). The
degree of cytotoxicity is dependent upon a number of factors
including, but not limited to: the activation state of NK cells,
the affinity of CD16, and inhibitory signaling via KIRs (Becknell
and Caligiuri, 2008). This manuscript reviews recent findings in
clinical and preclinical trials related to each of these factors and
provides a hypothesis regarding the potential for genetic screen-
ing of patients for favorable KIR/KIR-L and FcR genotypes for
immunotherapeutictreatmentof NBLinthecontextof NK-based
and mAb-mediated cancer immunotherapy. This neuroblastoma
(NBL)-based hypothesis may potentially apply to other cancers
for which mAb-mediated treatment has been shown to involve
Natural killer cells are large granular lymphocytes of the innate
immune system responsible for elimination of infected and trans-
formed cells as well as cytokine production. NK cells recognize
and destroy target cells via immune synapses formed through
surface-expressed receptors on the NK cells and corresponding
ligands on target cells (Orange, 2008). NK cell-mediated cytotox-
icity is directed toward specific target cells, based on the balance
of recognition of appropriate membrane structures by activating
and inhibitory receptors expressed on the NK cell (Leung, 2011).
The mechanisms of destruction are multi-modal: the release of
sion of Fas ligand (Fas-L) and TNF-related apoptosis inducing
ligand (TRAIL) are mechanisms used by NK cells to kill target
cells (Zompi and Colucci, 2005). NK cells can further shape the
immune response by secreting cytokines (such as IFN-γ, TNF-
α, and GM-CSF), and chemokines (for example MIP-1α and
RANTES; Oliva et al., 1998; Biron et al., 1999). The level of NK
response is ultimately determined by the balance of signals from
activating and inhibitory receptors (Moretta et al.,2005). NK cells
express a variety of activating (NCRs, NKG2D, KIRs, and CD16)
and inhibitory receptors (NKG2A/CD94 and KIRs; Farag and
are adhesion molecules (CD2 and LFA-1) and cytokine receptors
2003; Gubbels et al., 2011).
Antibody-dependent cell-mediated cytotoxicity is an impor-
tant anti-tumor mechanism of the innate immune system, medi-
ated by leukocytes with FcRs (NK cells,monocytes,macrophages,
and neutrophils). When a tumor is treated with a tumor-specific
mAb, the variable regions of the Fab portions of the mAbs bind
to the antigens on the tumor. The Fc regions of the tumor-bound
mAbs project from the tumor cell surface allowing interactions
with effector cells that express FcRs. The binding of many mAb
moleculestothesurfaceof atumorcellcreatesalatticeof exposed
Fc regions allowing for multiple Fc–FcR interactions. When mul-
simultaneously, immunoreceptor tyrosine-based activation motif
(ITAM)-mediated downstream signaling events occur that lead
to triggering of cytotoxic mechanisms and the destruction of
mAb-coated tumor cells (Ravetch and Bolland, 2001; Farag et al.,
Leukocytes express a variety of receptors from the FcR fam-
ily. The most important activating FcRs for ADCC include CD16
(FcγRIIIa; expressed primarily on NK cells) and CD32 (FcγRIIa;
jahn and Ravetch, 2008). CD16 and CD32 bind to the Fc portion
of human immunoglobulin molecules with the highest affinity
for the IgG1 isotype (Jefferis, 2007); thus human mAbs of the
IgG1 isotype induce a more robust ADCC response compared to
approved for clinical application are of the human IgG1 isotype
(Schrama et al., 2006).
Theimportanceof FcRsinmAb-basedcancertherapyhasbeen
previously demonstrated with the application of multiple tumor-
specific mAbs in both preclinical and clinical settings. Using mice
ity of therapeutic mAbs was diminished in FcγR knockout mice
compared to wild-type mice, indicating the importance of FcRs
in tumor cell clearance . Studies have demonstrated the impor-
tance of ADCC as a tumor clearing mechanism in mAb therapies
(Basham et al.,1988;Primus et al.,1994). Many therapeutic mAbs
currently used clinically to treat cancer, such as Rituximab (anti-
CD20), Trastuzumab (anti-HER2), Cetuximab (anti-EGFR), and
ch14.18 (anti-GD2), likely utilize ADCC as an anti-tumor mech-
anism, although it is difficult to determine the necessity for NK
cell-mediated ADCC in humans (Adams and Weiner, 2005).
Several preclinical studies had shown that IL2, a potent activator
of NK cells, augments NK-mediated ADCC when used to treat
NK cells in vitro, and in vivo administration of IL2 increased the
ability of circulating NK cells from cancer patients to mediate
Frontiers in Pharmacology | Pharmacology of Anti-Cancer Drugs
May 2012 | Volume 3 | Article 91 | 2
Page 3
Koehn et al.KIR and FcR in clinical-ADCC
(COG) combined mAb treatment with cytokine administration
(Yu et al., 2010). Patients that received then-standard therapy of
13-cis retinoicacid(CRA)alongwithanimmunotherapyregimen
of ch14.18 mAb, IL2, and GM-CSF showed improved response as
compared to the control group that received only CRA. There was
a significant improvement in 2-year overall survival (86 vs. 75%;
p =0.02) and 2-year event-free survival (66 vs. 46%; p =0.01) in
et al.,2010). Of note,a study previously conducted in Germany of
ch14.18 mAb treatment of children with NBL initially found no
therapeutic advantage to treatment with the ch14.18 mAb alone
(Simon et al., 2004). A long term follow-up of the German study
did demonstrate an advantage in survival, but not in event-free
survival (considered to be a more direct indicator of anti-tumor
effect of the therapy), for those children that received the ch14.18
(Simon et al., 2011). Importantly, this German study employed
ch14.18 alone, without the administration of IL2 and GM-CSF,
which suggests that the clinical benefit realized in the COG study
was due, at least in part, to the activation of innate immune cells
by the addition of IL2 and GM-CSF.
To further advance the therapeutic benefits of this combi-
natorial therapy, hu14.18-IL2 IC was developed from the well-
characterized ch14.18-IL2 IC (Yamane et al., 2009). Ch14.18-IL2
was constructed by fusing the gene sequence for human IL2
to the human Cγ1 gene at the carboxy-terminus of each IgG1
heavy chain of ch14.18 mAb (Gillies et al., 1992). This genetic
linking enables the delivery of IL2 to the tumor microenviron-
ment (Lode et al., 1998a; Johnson et al., 2007). In contrast to
ch14.18-IL2, the antibody portion of hu14.18-IL2 has been 98%
humanized to minimize anti-mouse antibody responses (Yamane
et al., 2009). Hu14.18-IL2 IC is a next generation anti-GD2ther-
apeutic agent that holds promise in NBL treatment. In mice,
hu14.18-IL2 IC exhibits superior anti-tumor effects compared to
simultaneous administration of similar amounts of hu14.18 mAb
et al., 2005). The anti-tumor effect is primarily NK cell-mediated
(Lode et al., 1998b) and more pronounced in mice with non-
bulky disease (Neal et al., 2004b). As demonstrated in a murine
NBL study (Neal et al., 2004a), increased Major Histocompatibil-
ityComplexClassI(H-2classI,themouseequivalentof HLA-Iin
humans, KIR-L) expression appears to be a mechanism by which
tumor cells can escape hu14.18-IL2 IC-induced, NK-mediated,
immunotherapy. A similar escape mechanism has been shown in
B cell-lymphoma upon Rituximab treatment (Borgerding et al.,
2010), suggesting that ligation of inhibitory receptors (KIRs) on
The superior anti-tumor effects of hu14.18-IL2 IC (over the
taneously) may be due, in part, to contributions from IL2Rs that
are able to interact with IL2 molecules uniquely presented on the
surface of 14.18-IL2 IC-treated tumor cells. Gubbels et al. (2011)
used an NK cell line (NKL) that expresses little or no CD16, to
(in vitro) to tumor cells via the NK cells' IL2Rs (Figure 1). Also,
interaction with hu14.18-IL2 IC-coated tumor cells via the NK
molecules, resulting in the formation of an activating immune
synapse (AIS) necessary for the subsequent destruction of tumor
FIGURE 1 | 14.18-IL2 IC increases conjugate formation between M21
blocked with an anti-CD25 (IL2R α-chain) mAb in flow cytometry
conjugate assays. M21 and NKL cells were dyed with BODIPY and CFSE
respectively, incubated together with the depicted treatments and analyzed
for conjugate formation. huKS-IL2 IC, which recognizes EpCAM not GD2, was
+tumor cells) and NKL cells, and conjugate formation can be
added to demonstrate specificity of the hu14.18-IL2 IC. Pre-treatment with
blocking anti-CD25 mAb almost completely abrogates conjugate formation.
Numbers in dot plots indicate percentage of total counted events in each
quadrant, with the upper right quadrant indicating 2-color conjugate events.
The results are representative of three independent experiments (Reproduced
here, with permission, from Gubbels et al., 2011).
May 2012 | Volume 3 | Article 91 | 3
Page 4
Koehn et al.KIR and FcR in clinical-ADCC
of hu14.18-IL2ICmaybeattributed,inpart,toitsabilitytofacili-
of NK cells can increase the expression of activating receptors
on the NK cell thereby tipping the balance in favor of activation
and reducing the inhibition mediated by KIR/KIR-L interactions
(Huenecke et al., 2010). Taken together, these data imply that NK
cells expressing GD2via their FcRs, via IL2R-mediated events, or
by utilizing both FcRs and IL2Rs simultaneously.
of hu14.18-IL2ICinchildrenwithrecurrentorrefractorydisease.
A daily dose of 12mg/m2was given intravenously for three con-
secutive days every 28days. While no responses were noted in the
15 patients with bulky disease detected by computed tomography
(CT) scan or magnetic resonance imaging (MRI),5 of 24 patients
with less-bulky disease, evaluable only by bone marrow biopsy
or Iodine-131-Meta-Iodobenzylguanidine (131I-MIBG) scintigra-
phy, had complete responses. Two other patients with less-bulky
disease showed clear evidence of anti-tumor effect, but did not
quite meet the stringent response criteria of the study. The dose
limiting toxicities of hu14.18-IL2 IC included capillary leak,pain,
and allergic reaction (Osenga et al.,2006). The difference between
clinical activity in the patient group with bulky disease vs. the
group with less-bulky disease was significant (p =0.03) and was
consistent with results from preclinical studies in tumor-bearing
smaller tumors at the time treatment was initiated (Neal et al.,
INFLUENCE OF FcR POLYMORPHISMS ON ADCC ACTIVITY
Studies of people expressing polymorphic variants of FcRs have
demonstrated that responses in mAb-based cancer therapy vary
depending on FcR polymorphisms. In humans, the FcR found
on NK cells, CD16, displays a single nucleotide polymorphism
(SNP) resulting in a different amino acid in the IgG-binding
domain at position 158. Either phenylalanine (F) or valine (V)
is present, which is associated with a lower or a higher affin-
ity for the Fc portion respectively. Subsequently, studies using
the tumor-targeted mAb Rituximab have shown that the V/V
genotype has the highest binding affinity to IgG1 isotype and
initiates more robust ADCC activity in vitro. Furthermore, a pos-
itive correlation has been drawn between a V/V genotype and
superior clinical response to Rituximab. In studies of Ritux-
imab in Non-Hodgkin's lymphoma (Cartron et al., 2002; Weng
and Levy, 2003), patients with the high affinity V/V genotype
showed a higher complete or partial response rate of 96% com-
pared to 62% for patients with the intermediate (F/V) or low
affinity (F/F) genotypes. Thus, carrying the high affinity CD16
genotype can be used as a positive predictive marker for better
response to Rituximab, and likely to other human mAbs of an
IgG1 isotype.
Most, but not all, studies on Rituximab, Trastuzumab, and
Cetuximab demonstrated greater clinical benefit in patients with
high affinity V/V genotypes of CD16 (Cartron et al., 2002; Weng
and Levy, 2003;Zhang et al., 2007; Musolino et al., 2008;Tay-
lor et al., 2009). In addition, there is also a benefit of having
a genotype for a high affinity CD32, the FcR found on neu-
trophils and monocytes/macrophages. CD32 also has a SNP in
humans consisting of two alleles. These alleles differ in the IgG-
binding domain at position 131, where either a lower affinity
arginine (R) or a higher affinity histidine (H) is present. For
CD32, the H/H genotype has the highest affinity binding to the
IgG1 isotype and initiates more robust ADCC in vitro. Similar
to CD16, the high affinity CD32 subtype (H/H) has also been
associated with a greater clinical response to the above men-
tioned therapeutic mAbs (Weng and Levy, 2003; Zhang et al.,
2007;Musolino et al., 2008; Taylor et al., 2009). Collectively, these
studies suggest that the in vivo efficacy of therapeutic mAbs is,
at least in part, dependent on the affinity of FcRs for IgG1, con-
sistent with a major role for in vivo ADCC as the mechanism of
INHIBITORY KIRs AND NK CELL RESPONSES
Killer immunoglublin-like receptors are cell surface proteins of
NK cells that regulate NK cell activation and function. Inhibitory
KIRs are distinguished from activating KIRs by the inclusion
of an immunoreceptor tyrosine-based inhibitory motif (ITIM)
in the cytoplasmic signaling domain, leading to a potent inhi-
bition of multiple cell processes upon engagement (Purdy and
Campbell, 2009; Leung, 2011). While many ligands for activat-
ing KIRs are not well established, inhibitory KIRs recognize Class
I human leukocyte antigen (HLA-I) molecules (KIR-L), which
are expressed by all nucleated cells. The expression of inhibitory
KIRs helps prohibit NK effector function against HLA-expressing
autologous normal cells (Vilches and Parham, 2002). Downreg-
ulation of HLA is a mechanism by which virally infected and
transformed cells evade T cell recognition (Vilches and Parham,
2002). However in the absence of normal HLA-I expression, NK
cells are not inhibited through their KIRs, potentially resulting in
lysis of autologous cells (Kärre, 2002; Vilches and Parham, 2002).
NK cells are often described as natural effector cells against virally
infected and transformed autologous cells (Purdy and Camp-
bell, 2009) and much of this responsiveness is dictated by the
balance of activating signals with the engagement of inhibitory
KIRs (Kärre, 2002; Orr et al., 2010). Thus, the effector func-
tion of NK cells is tightly regulated by inhibitory KIR signal-
ing and is of great importance to NK-mediated immunotherapy
Killer immunoglublin-like receptor in humans bind to spe-
cific HLA Class I molecules (KIR-L) coded for by the A, B, and
C loci (Velardi,2008). Four inhibitory KIRs: KIR2DL1,KIR2DL2,
KIR2DL3,andKIR3DL1havereceivedalotof attentioninvarious
cell therapy settings (Purdy and Campbell, 2009). The impor-
tance of KIR/KIR-L interaction for the anti-cancer activity of NK
cells was demonstrated in the setting of allogeneic hematopoietic
stem cell transplant (HSCT). In HLA-haploidentical transplanta-
tion patients with acute myeloid leukemia (AML), Ruggeri et al.
evaluated the response of leukemia patients where the HLA Class
I expression of KIR ligands (KIR-L) on donor and recipient indi-
cated that donor NK cells might not all be inhibited by recipient
HLA (designated as "KIR-Ligand incompatibility" in the "GVH
Frontiers in Pharmacology | Pharmacology of Anti-Cancer Drugs
May 2012 | Volume 3 | Article 91 | 4
Page 5
Koehn et al.KIR and FcR in clinical-ADCC
a survival advantage if they had a KIR-Ligand incompatibility.
Five years post transplant 100% of AML patients with a missing
expressed KIR-Ls for all donor NK cells (Ruggeri et al., 2002). An
of KIR-L incompatibility in AML patients after transplant. Of the
112 HLA-haploidentical transplants in high-risk AML patients,
those who were KIR-L incompatible for their transplant had sig-
nificantly better event-free survival compared to patients without
KIR-L incompatibility (67%; n =51 vs.18%; n =61 respectively;
p =0.02). Thus, improved leukemia control can be conferred by
alloreactive donor NK cells, in AML patients whose cells are KIR-
L incompatible in the GVH direction. In contrast, in these same
reports,there was no benefit noted for a missing KIR-L in patients
with acute lymphoid leukemia (ALL).
More recently, Leung et al. (2007) proposed a separate way of
analyzing these allogeneic KIR relationships. By first characteriz-
ing the genotype for the inhibitory KIRs of the donor (KIR2DL1,
KIR2DL2, KIR2DL3, and KIR3DL1), and then genotyping the
HLA Class I KIR ligands of the recipient, one could determine
whether donor NK cells contained at least one KIR for which the
"KIR/KIR-Ligand mismatch"). In those transplant recipients with
of thetransplantedNKcellsthatcouldnotbeligatedbytheHLA-I
molecules on the patient's cells. In this analysis, pediatric patients
with AML or ALL were found to have a survival advantage if they
and their allogeneic donor were KIR/KIR-L mismatched (Leung
et al., 2004).
The initial clinical analyses of KIR/KIR-L mismatch were
restricted to allogeneic HSCT (Ruggeri et al., 2002; Hsu et al.,
2005;Vivier et al., 2011) and allogeneic adoptive NK infusions
(Miller et al., 2005; Bachanova et al., 2010;Geller et al., 2011).
KIR genes and HLA-I genes are inherited independently because
they are encoded on different chromosomes (19q13.4 and 6p21.3
respectively; Purdy and Campbell, 2009). Moreover, there is a
great degree of polymorphism of these genes among individu-
als (Vilches and Parham, 2002; Purdy and Campbell, 2009). The
independent segregation and stochastic expression of KIR and
HLA-I genes can cause some individuals to have NK cells that
express KIRs for which that same individual has no correspond-
ing HLA (KIR-L). This situation has been designated by Leung
and colleagues as KIR/KIR-L mismatch. Various reports of clini-
cal trials have suggested that an autologous KIR/KIR-L mismatch
occurs in approximately 60% of patients (Moretta and Moretta,
Leung et al. (2007) demonstrated a clinical benefit of autologous
KIR/KIR-L mismatch in pediatric patients that received ASCT for
been implicated as a favorable prognostic factor in high-risk NBL
patients following autologous HSCT. In a retrospective study of
169 patients, Venstrom et al. (2009) found a significantly lower
risk of death and disease progression in patients lacking one or
moreautologousKIR-L(46and34%,withp =0.007andp =0.047
respectively) compared to patients who were fully autologous
KIR/KIR-L matched.
GENOTYPING FOR FAVORABLE KIR AND FcR ALLELES IN
mediated anti-tumor responses that can be independent of T cells
escape hu14.18-IL2 IC therapy by increasing MHC-I expression,
a mechanism capable of down regulating NK cell function via the
mouse equivalent of inhibitory KIRs - the inhibitory Ly49 recep-
tors(Nealetal.,2004a).Furthermore,theadvantageof KIR/KIR-L
mismatch in allogeneic and autologous transplant setting has
been demonstrated (Ruggeri et al., 2002; Leung et al., 2007; Ven-
strom et al., 2009). These observations led us to hypothesize that
individuals with an inherited autologous KIR/KIR-L mismatch
basedontheknownimportanceof FcRpolymorphismsforhigher
affinity alleles in mAb therapy, that we would see a correlation
between responses to hu14.18-IL2 IC immunotherapy and geno-
types for high affinity polymorphisms for both CD32 and CD16
To test these hypotheses our lab analyzed the relationship
between FcR genotype and KIR/KIR-L match or mismatch status
with regard to the clinical response of patients following hu14.18-
IL2 IC therapy using patient samples from the phase II COG NBL
study (Delgado et al., 2010). We performed FcR and KIR/KIR-L
genotyping on DNA isolated from clinical samples from patients
enrolled in this study (n =38). For these analyses, an individual's
KIR/KIR-L status is determined by genotyping for the presence or
absence of inhibitory KIR genes (2DL1, 2DL2, 2DL3, and 3DL1)
as well as their ligands, allelic groups of HLA genes: HLA-C1,
HLA-C2,and HLA-Bw4. The detection of inhibitory KIR genes is
currently done in our laboratory by a SYBR Green Real Time PCR
reaction with primers designed to amplify a specific gene locus
followed by analysis of the melting curve (Vilches and Parham,
the polymorphism of HLA genes is tremendous, the recognition
byKIRsdistinguishesfamiliesof HLAallelesinarelativelysimple,
bi-allelic fashion. In order to specifically address the broad HLA
specificities (HLA-C1, HLA-C2, and HLA-Bw4) as recognized by
KIRs, typing methods include PCR amplification with sequence-
specific primers (PCR-SSP),PCR amplification using a sequence-
specific oligonucleotide probe (PCR-SSOP), and sequence-based
typing (SBT).Additionally,SYBR Green Real Time PCR methods,
similar to that described above for KIR genotyping, can be used
et al., 2011).
When we evaluated the KIR/KIR-L genotype of patients, we
found a statistically significant difference (p =0.03) between the
outcome of patients that had an autologous KIR/KIR-L mismatch
and those that were KIR/KIR-L matched. Upon closer evaluation,
our data showed that of the seven patients that showed improve-
ment, all seven inherited an autologous KIR/KIR-L mismatch.
strationof autologousKIR/KIR-Lstatusasapredictorof response
to immunotherapy beyond that shown previously in the setting
of adoptive allogeneic BMT or NK cell transfer or autologous
May 2012 | Volume 3 | Article 91 | 5


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POSITION DESCRIPTION:The Air/Ocean Export Agent is responsible for executing all functions related to the successful operation of this position and to provide top notch customer service with continual improvement in mind.
MAIN RESPONSABILITIES:- Receive and process export shipments via trucking lines, airlines and steamship companies.- Communicate effectively and timely via phone and email.- Take booking requests and customer service calls throughout the day.- Confirm rates every export shipment prior to booking.- Create proper and complete export documentation and send pre-alerts.- Request and review export documents.- Understand and follow standard operating procedures to insure compliance.- Proactively notify all necessary parties of ANY delays regarding arrival or delivery of their cargo.- Negotiate trucking rates, review and approve all truck bills for payment.- Dispatch truckers to customers to pick up freight and monitor its arrival for consolidation.- Create all required documentation.- Review and meet deadlines listed in Operations SOP.- Cross train as time permits.
QUALIFICATIONS:- High School Diploma- 3-4 years Export Agent Experience (both Ocean and Air), function required consisting of all elements of the export process and related documents.- Three years college is preferred.- Solid knowledge of domestic and international geography including countries, major cities and ocean ports along with basic knowledge of U.S. Regulatory Laws.- IATA DG certification will be considered an asset.- TSA training will be also considered a must, and IACSC training will be considered a valuable asset- Bilingual (Spanish/English)- Knowledge and understanding of US Export Compliance Regulations- Solid understanding of international logistics, cargo movement and related requirements- GREAT customer service- Positive attitude- Willingness to grow and develop skills for long-term career- Good memory- Must be detail oriented, thorough and accurate and have the ability to efficiently solve problems- Ability to establish priorities and accomplish multiple tasks, must be organized- Ability to work with demanding deadlines- Get it done attitude- Excellent communication skills, both verbal and written- Ability to work independently as well as part of a team- Looks for ways to improve processes and service- Shares best practices and knowledge.- Strong PC skills- Proven analytical and problem solving skills- Work effectively via phone, fax, e-mail- Proficient in common software programs such as: Excel, Word, PowerPoint, Cargo movement software, MS Outlook, etc.
HOW TO APPLY:Send an email as follows:- "Export Agent Position - First & Last Name" in the subject line of the email- Attach resume (pdf or Word format)- Include the following in the body of your email:-- Salary Requirements-- Definitions of the following acronyms: FMC, LCL, FCL, BAF, GRI, ECCN, SED, SLI, B/L, MBL, HBL, CASS, IATA, STA, ECCN, SED, SLI, B/L, MAWB, HAWB, POD, OAG
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Enjoy what we do? Support Between the Ropes on Patreon! Your generous donation will help keep our lights on, and make it possible for us to do even more! Wrestling fans everywhere will thank you. WWE ESPN is covering SummerSlam. That's a pretty big deal, even if it's only ex-announcer Jonathan Coachman on the ground in Brooklyn as a reporter. ...Read More »
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ROH 13th Anniversary Results & Reaction
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The WWE Television Champion Dolph Ziggler?
Jim Ross on his most recent podcast in the preamble to his interview with Eric Bischoff (at 19:20 mark) suggests the creation of a "new" WWE Television Title. His choice as the eventual winner of this title decided through a multi-week tournament to crown the new champion is Dolph Ziggler. On the surface this seems like a heck of an ...Read More »


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Just Kidding ! But hubby says it's time to pay attention to him!
Enjoy killing this one ladies !
Thanks amber...I have soo many pictured of him...I could probably kill this thread with all of them, but I will save for the future haha :)
A+R=happily married 17June2011
Billie Paige 25June2012 and Ryan James 04August2004
2 time Thread Killer and looking for a 3rd!


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Lisa Burns and Louise Burns as the Grady sisters on the set of The Shining.
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Eric Idle during the filming of the 'The Journey of The Olympic Flame'-sketch for Monty Python's Fliegender Zirkus.
Robert Shaw, Roy Scheider, Steven Spielberg and Richard Dreyfuss
Paul Shrader, Martin Scorsese and Robert DeNiro
Screenwriter Paul Shrader, Martin Scorsese and Robert DeNiro having a laugh on the set of Taxi Driver.
Photo by Steve Schapiro.


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Would you like to save names or email namesto a friend?
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First name content excerpted from The Complete Idiot's Guide to 30,000 Baby Names © 2005 by
Marcia Layton Turner.
this book online or call 1-800-253-6476.
Last name content copyright © 2006 Patrick Hanks.
First name origins & meanings:
First name variations: Cass, Gaspar, Gaspard, Gasparo, Gasper, Jasper, Kaspar, Kasper, Caspar, Gasper, Gaspare, Jasper, Caspar, Gaspard, Gasparo, Jaspar, Kaspar, Kasper, Gasparas, Gaspari, Gasparo, Gazsi, Gaspar, Caspar, Kasp, Kasper, Kaspar
Last name origin & meaning:
German and Slavic: from the personal name Casper or
Kaspar, which was especially popular in central Europe up to
the 18th century. Originally from Persian kaehbaed,
khazana-dar, or ganjvaer, all meaning 'treasure bearer',
it was ascribed by popular tradition in Europe to one of the three
Magi. Their supposed remains were taken to Cologne from Constantinople
in the 12th century. See also Baltazar and Melchior.
Famous people who gave their babies this name:
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daddy wants 2 get me wetdaddy wants 2 get me wet July 31, 2015 daddysTINY
pool time with daddy is fun because he gets me all wet and i get to bounce all around on daddy. @daddydan loves to play with me in the pool. just me and him. when mommy is sleeping, we go down to the pool and swim and stuff. daddy called me to the stairs to »


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|Project Name
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|Copywriting, SEO
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|200 custom 200+ word article needed
|...write 200 articles for targeting two adult related keywords. The articles will be 200+ in word length
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|Feb 1, 2010
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|Ten 200-300 word travel related articles
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|Five 200-300 Word travel related articles
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|100 or 200 healthcare related articles (350 to 400 word each)
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|162 x 200-300 word articles for finance related keywords
|...- Articles will be 200+ words each depending on my requirements(excluding article title). - Articles... (you may not reuse them!) - Each and every article MUST PASS COPYSCAPE and dupefreepro
|Copywriting, Blog, Articles, Reviews, Article Rewriting
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|200 Word Article
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|50 short, 200-word articles
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|200 word article for SEO
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|Article writing Dental related
|...writer / ghost-writer to write 500-1000 word dental health related articles for blogs targeted to end users...PLEASE NOTE: YOU MUST BE ABLE TO WRITE ABOUT DENTAL RELATED TOPICS AND MAKE THEM INTERESTING!! This will...something like the recent kid from India who had 200+ teeth removed. We want stuff that will really
|Blog, Ghostwriting, Articles, Medical Writing, Newsletters
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|100 x 200 word articles at $0.50 per article
|...need 100 articles on insuranvce. they will be 200 word each. They will be used on a website and I will...tool. All articles are on car insurance or related topics. I suggest that you do a little research...will be 200 word > keywords will be provided. > keywords must be used 2-3 times in each article > Keyword
|Blog, Technical Writing, Articles
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|Write a 200-250 word article
|Write an article each of around 200-250 words about hotels in the UK and how by using our company they
|Technical Writing, Articles, Academic Writing, Article Rewriting
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|Game Related Article Reviews Needed
|...reviews: 17 Game Reviews - 200-250 Words 9 Anime Reviews from either Books or TV - 200-250 Words 9 Manga Reviews...either Books or TV - 200-250 Words Total: 35 Reviews All reviews should be 200-250 words, and I will...or 2 samples of GAME, Anime Manga RELATED reviews, along with word count and delivery timeframe. IMPORTANT:
|Copywriting, Academic Writing, Article Rewriting
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|Blog, Ghostwriting, Articles, Product Descriptions, Article Rewriting
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|200 x 200 Word Articles
|Need 200 x 200 words, finance related. Need these ASAP. Will accept in batches of 20 at a time, so 10
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|Article Article Writers Needed 200 Rs Per Article
|...experienced article writers. Topics will vary and will be related to online education and it related topics...be used for Article marketing and PR purpose. Payout is 200 Rs per 500 word article.
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|Article writer for health related site
|...one article a day for the next month. The articles should be around 200-300 words and are related to health...health related issues & products. Requirements: - you write PERFECT English - please submit an...an example of article you wrote (no article = no response) - every article must pass copyscape - as soon
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|Ten (10) 200-600 word original articles
|...looking for someone to compile / write articles related to a list of different keywords which I will provide...bidder. I will provide the keyword sets and key word density ranges. These articles are for creating...in creating 100 - 200 one page articles, ranging between 200 - 800 words per article, containing the various
|Copywriting, Technical Writing, Academic Writing, Article Rewriting
|Mar 23, 2004
|Mar 23, 2004Ended


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Bark to School Again!
Back to school time is not only stressful for parents and children, but your pets too! They are used to having companionship throughout summer and they can experience separation anxiety. (Which could include anything from destructive behavior, hurting themselves, or endless barking.) One way to curb this issue is to keep them occupied while you and your family are away.
We offer an array of toys to keep them occupied during those long work/school days. Get hims toys like a Starmark© Treat Ball or Kong® toy that they can chew and can stuff their favorite treats in and they have to figure out how to get them out! Make sure he has plenty of toys to choose from and that nothing is to small that they could choke while you are away. For those more stubborn dogs or messy puppies we also carry crates to protect them and your home while you are out!
Maybe your kids are going away to college and are bummed about having to leave their pet. Most campus dorms and college apartments don't allow pets, but they do allow fish! We carry an array of fish tanks, accessories, and fish to help them cope with those homesick blues. Also, all this month ALL GloFish® are only $4.99 at all locations!
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Appointments Required
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Our Justin Alexander Trunk Show is this weekend! With ten percent discounts on all of our Justin Alexander gowns you will not want to miss out! Call and schedule your appointment with us today while space lasts!
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